Signal transduction inhibitors

The microbial product staurosporine is a non.sclcciivepav tcin tyrosine kinase inhibitor uf EGFR kinase. A simpitt dianilinuphthalimide. analogue I. is a potent and sclcctlw inhibitor of EGFR kina.se.-  

Two small inhibitors of cyclin-dependent kinases, flavo-peridul and UCN-OI (hydroxystaurosporine). are in clinical trials. Ravoperidol is a competitive inhibitor of ATP. Its 

Ras protein is central among the many oncogene- or pro-tooncogene-encoded proteins that serve as signal transducers in the pathway from the outer membrane to the nucleus of cells. It acts as a common relay point for signals from various 

Imatinib. Imatinib. Glcevcc. ST1571. N-13-14-(4-methyl-pipcra/inomethyI)-benzoyluniido -2-tiiethylphenyl -4- 

Imatinib is indicated for chronic myelocytic leukemia. Il acts by inhibiting the tyro.sine kina.se BRC-ABL. thus ptc-venting it from arresting apoptosis. This agent is well ab-.sorbed orally, and the maximum concentration in blood r achieved within 2 to 4 hours. Il is 95% bound to. senim proteins. The major metabolite results from N-demelh l-alion. Elimination half-times are 18 hours for imatinib anl 40 hours for the N-demelhyl metabolite. Excretion is mainly in feces. 

---

Thiophene, 2,2-bithiophene, and 2,2, 5, 2"-terthiophene derivatives from Chinese medicinal plants as oncogene signal transduction inhibitors (proteinki-nase C inhibitors) 99PAC1101. 

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

Weigele M, Bohacek R, Jacobsen VA, Macek K, Yang MG, Kawahata NH, Sundaramoorthi R, Wang Y, Takeuchi CS, Luke GP, Metcalf CA III, Shakespeare WC, Sawyer T. Synthesis of phosphono-containing amino acid derivatives and peptides as signal transduction inhibitors. PCT Int Appl W099/24442, 1999. 

Introduction Cyclooxygenase-2 Antiangiogenesis Agents Signal Transduction Inhibitors Ras Farnesylation Inhibitors Cell Cycle Inhibitors Promotors of Apoptosis Conclusions References... 

Nilotinib is a phenylaminopyrimidine structurally related to imatinib (Glivec) . It is a signal transduction inhibitor that potently and selectively inhibits tyrosine kinases. It was developed (Phase 11/111) for treatment of leukemias. ... 

P. Nicklin. 1996. Second-generation anti-sense oligonucleotides Structure-activity relationships and the design of improved signal transduction inhibitors. Biochem. Soc. Trans. 24 630-637. 

Despite their important specificity, toxicity and side effects similar to those of the standard cytotoxic chemotherapeutic approaches can also occur with signal transduction inhibitors. 

Park BJ, Whichard ZL, Corey SJ (2012) Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines—lessons for design of combination targeted therapy. Cancer Lett 320(1) 104-110... 

Burke, T. R. Jr., Yao, Z.-J., Smyth, M. S., and Ye, B. (1997) Phosphotyrosyl-based motifs in the structure-based design of protein-tyrosine kinase-dependent signal transduction inhibitors. Curr. Pharm. Des. 3, 291-304. 

Leary A, Johnston SR. Small molecule signal transduction inhibitors for the treatment of solid mmors. Cancer Invest. 2007 25 347-365. 

Shokat K, Velleca M. Novel chemical genetic approaches to the discovery of signal transduction inhibitors.(see comment). Drug Discov. Today 2002 7 872-879. 

Burke TRJ, Yao Z-J, Liu D-G, Voigt J, Gao Y. Phosphoryltyro-syl mimetics in the design of peptide-based signal transduction inhibitors. Biopolymers 2001 60 32-44. 

---